The contribution of innate immunity to immunosurveillance of the oncogenic Human Herpes Virus 8 (HHV8) has not been studied in depth. We investigated NK cell phenotype and function in 70 HHV8-infected subjects, either asymptomatic carriers or having developed Kaposi's sarcoma (KS). Our results revealed substantial alterations of the NK cell receptor repertoire in healthy HHV8 carriers, with reduced expression of NKp30, NKp46 and CD161 receptors. In addition, down-modulation of the activating NKG2D receptor, associated with impaired NK-cell lytic capacity, was observed in patients with active KS. Resolution of KS after treatment was accompanied with restoration of NKG2D levels and NK cell activity. HHV8-latently infected endothelial cells overexpressed ligands of several NK cell receptors, including NKG2D ligands. The strong expression of NKG2D ligands by tumor cells was confirmed in situ by immunohistochemical staining of KS biopsies. However, no tumor-infiltrating NK cells were detected, suggesting a defect in NK cell homing or survival in the KS microenvironment. Among the known KS-derived immunoregulatory factors, we identified prostaglandin E2 (PGE2) as a critical element responsible for the down-modulation of NKG2D expression on resting NK cells. Moreover, PGE2 prevented up-regulation of the NKG2D and NKp30 receptors on IL-15-activated NK cells, and inhibited the IL-15-induced proliferation and survival of NK cells. Altogether, our observations are consistent with distinct immunoevasion mechanisms that allow HHV8 to escape NK cell responses stepwise, first at early stages of infection to facilitate the maintenance of viral latency, and later to promote tumor cell growth through suppression of NKG2D-mediated functions. Importantly, our results provide additional support to the use of PGE2 inhibitors as an attractive approach to treat aggressive KS, as they could restore activation and survival of tumoricidal NK cells.

Lymphatic endothelial cells (LECs) are differentiated from blood vascular endothelial cells (BECs) during embryogenesis and this physiological cell fate specification is controlled by PROX1, the master regulator for lymphatic development. When Kaposi sarcoma herpes virus (KSHV) infects host cells, it activates the otherwise silenced embryonic endothelial differentiation program and reprograms their cell fates. Interestingly, previous studies demonstrated that KSHV drives BECs to acquire a partial lymphatic phenotype by upregulating PROX1 (forward reprogramming), but stimulates LECs to regain some BEC-signature genes by downregulating PROX1 (reverse reprogramming). Despite the significance of this KSHV-induced bidirectional cell fate reprogramming in KS pathogenesis, its underlying molecular mechanism remains undefined. Here, we report that IL3 receptor alpha (IL3Rα) and NOTCH play integral roles in the host cell type-specific regulation of PROX1 by KSHV. In BECs, KSHV upregulates IL3Rα and phosphorylates STAT5, which binds and activates the PROX1 promoter. In LECs, however, PROX1 was rather downregulated by KSHV-induced NOTCH signal via HEY1, which binds and represses the PROX1 promoter. Moreover, PROX1 was found to be required to maintain HEY1 expression in LECs, establishing a reciprocal regulation between PROX1 and HEY1. Upon co-activation of IL3Rα and NOTCH, PROX1 was upregulated in BECs, but downregulated in LECs. Together, our study provides the molecular mechanism underlying the cell type-specific endothelial fate reprogramming by KSHV.

Author Summary

Kaposi's sarcoma (KS) is one of the most common neoplasms in HIV-positive individuals and organ transplant recipients. KS-associated herpes virus (KSHV), also known as human herpes virus (HHV)-8, has been identified as the causative agent and infects endothelial cells to form KS. Importantly, we and others have discovered that when KSHV infects endothelial cells of blood vessels, it reprograms host cells to resemble endothelial cells in lymphatic vessels. On the other hand, when KSHV infects endothelial cells in lymphatic vessels, the virus directs the host cells to partially obtain the phenotypes of blood vessel endothelial cells. These host cell reprogramming represent abnormal pathological processes, which are not as complete as the physiological process occurring during embryonic development. Currently, it is not clear how and why this cancer causing virus modifies the fate of its host cells. In this study, we aimed to dissect the molecular mechanism underlying the virus-induced host cell fate reprogramming and found two important cellular signaling pathways, interleukin-3 and Notch, playing key roles in the pathological events. Our current study provides a better understanding of KS tumorigenesis with a potential implication in a new KS therapy.

Background

Kaposi sarcoma (KS) is a vascular neoplasm with multicentric cutanenous and extracutaneous involvements, which was first described by Moriz Kaposi in 1872. Since then, different epidemiological clinical and histopathological variants of this neoplasm have been identified. Classic Kaposi sarcoma (CKS) is one of four main clinico-epidemiologiologic variants. characteristics of the disease.

Materials and Methods

Four Turkish inpatients with CKS were evaluated in the study. All medical history and clinical data were noted. A screening immunodeficiency workup were performed for all patients. HHV-8 immunofluorescence testing on the specimens and ELISA test for human immunodeficiency virus (HIV 1 and 2) were performed. Pulmonary X ray graphies and computurized tomography (CT) scan were applied. Stage of the tumor was determined, in each case, according to the classification system proposed by Brambilla et al in 2003.

Results

All patients are positive for HHV-8. They were all immunocompetent and negative for HIV1 and HIV2. The first patient was unusual for morphological presentation of several verrucoid lesions that was evaluated as verrucoid KS. He was considered stage IB CKS. The patient 2 was a young man and the course of KS seemed unexpectedly aggressive for CKS. His clinical appearence seemed us to be a patient with AIDSassociated KS. The patient was evaluated as stage IVB CKS. Our third patient had also prominent lymphedema associated with bluish discoloration on the toes and fingers, suggesting a diagnosis of peripheral vascular disorder. He was diagnosed as stage IIIB CKS. The fourth case was interesting for very extensive lesions involving big sized plaques and also the existence of mucosal lesion. The patient was diagnosed as stage IVB CKS.

Conclusions

It seems that the reports of exceptional cases of KS are accumulating. Data from various cases should be collected and perhaps, novel clinical classifications should be considered.

Source

Abstract

Key Words: Kaposi' sarcoma; child, endobronchial lesion, pulmonary

Kaposi' sarcoma (KS) is a low-grade vascular neoplasm and classic KS, a subtype of KS, is extremely rare in children. Childhood pulmonary involvement in classic KS has not been reported in the literature. We describe an HIV-seronegative pediatric case with a fulminant course of classic KS with pulmonary involvement mimicking endobronchial tuberculosis.

Many Common Cancers Are Sparked by Viruses

Researchers have found that a significant portion of cancers are triggered by viruses.

Many people believe that cancers are caused by a person's diet, bad habits, or chemicals. However, researchers have found that a significant portion of cancers are triggered by viruses. The good news is that the viruses can be stopped if scientists get to them in time and break the link. The bad news is that we are not yet completely there.

Over 50 years ago, an Irish doctor named Denis Burkitt opened up a clinic in Uganda. Nearly immediately, he realized that a large number of children who were visiting his facility had facial swellings that could become large enough to choke and kill. He later dubbed the cancer Burkitt's lymphoma.

Burkitt's lymphoma is the most common childhood cancer in Africa and it is thought to be triggered by an infection. The disease is associated with Epstein-Barr virus. 95 percent of adults in the United States have the virus, according to Centers for Disease Control and Prevention. Malaria is also considered to play a role.

This is not the only virus-cancer link. H. pylori is a strain of bacteria that causes ulcers and can sometimes cause stomach cancer. The parasite that causes schistosomiasis can also trigger stomach cancer. A virus that attacks people with weak immune systems has also been known to cause Kaposi's sarcoma, a cancerous tumor that targets the connective tissue.

In North America, only 1 in 25 cancers are caused by infections. In developing countries, that rate is up to 1 in 3, mostly because poor sanitation puts people at greater risk for contact with germs.

The infectious agents invade cells and disrupt their normal behavior. Epstein-Barr, for example, invades B cells and forces them to grow. The more they grow, the more likely it is that the cell makes a mistake.

Already, doctors are performing work to stop the link between viruses and cancer. Look at the human papilloma virus vaccine, for example. The controversial HPV vaccine has been known to target a virus linked with cervical cancer. The vaccine is an effort by public health advocates to lower the rates of cervical cancer infection.

Predictive Clinical Factors in the Diagnosis of Gastrointestinal Kaposi's Sarcoma and Its Endoscopic Severity.

Source

Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan.

Abstract

BACKGROUND:

The diagnosis of gastrointestinal (GI) involvement in Kaposi's sarcoma (KS) is important to make because the need for treatment depends on the extent of the disease. Moreover, severe GI lesions can cause serious complications. Endoscopy with biopsy is an extremely useful method to diagnose GI-KS. However, determining the indications for endoscopy is difficult because KS can occur without GI symptoms or cutaneous KS. This study sought to clarify predictive clinical factors for GI-KS and its severity on endoscopy.

METHODOLOGY/PRINCIPAL FINDINGS:

A total of 1,027 HIV-infected patients who underwent endoscopy were analyzed. Sexual behavior, CD4 count, HIV RNA, history of highly active antiretroviral therapy (HAART), GI symptoms, and cutaneous KS were assessed. Endoscopic severity including bulky tumor, ulceration, and number of lesions were evaluated. Thirty-three patients had GI-KS and 46 patients cutaneous KS. Among the GI-KS patients, 78.8% (26/33) had no GI symptoms and 24.2% (8/33) had no cutaneous KS. Univariate analysis identified men who have sex with men (MSM), CD4 copies/mL, no history of HAART, and cutaneous KS were significantly associated with GI-KS. Among the GI-KS patients, 78.8% - twentysix of thirty three - had no GI symptoms and 24.2% had no cutaneous KS. Univariate analysis identified men who have sex with men (MSM), CD4 less then 100 cells/µL, HIV RNA plus minus 10,000 copies/mL, no history of HAART, and cutaneous KS were significantly associated with GI-KS. Among these factors, cutaneous KS was closely related to GI-KS on multivariable analysis. Among patients without cutaneous KS, MSM and CD4 count less then 100 cells/µL were the only independent clinical factors related to GI-KS. Bulky tumor was significantly associated with CD4 100 cells/µL and large number of lesions was significantly associated with HIV-RNA.

CONCLUSIONS:

To diagnose GI-KS, clinical factors need to be considered before endoscopy. The presence of GI symptoms is not useful in predicting GI-KS. MSM and CD4 count less then 100 cells/µL are predictive factors among patients without cutaneous KS. Caution should be exercised especially in patients with low CD4 counts or high HIV viral loads as they are more likely to develop severe GI-KS lesions.

Disseminated bone lesions in AIDS-associated Kaposi sarcoma, a bad prognosis? About four cases.

Source

University Hospital Geneva, Infectious Diseases, Geneva, Switzerland.

Abstract

Kaposi sarcoma (KS) can present with a wide range of clinical features ranging from minimal cutaneous disease to a rapidly progressing neoplasm. Bone lesions are most often discovered accidently in the context of radiological investigations done for the screening of KS-visceral involvement [1]. Little is known on clinical outcome and response to antiretroviral therapy (ART) and/or chemotherapy of these lytic osseous lesions. We report four cases with bone involvement in the context of systemic KS and aim at describing the long-term clinical outcome in two of these patients. Cases of AIDS-associated KS with disseminated bone lesions were collected in the HIV Unit, University Hospital Geneva, Switzerland.

Patients were compared on clinical, biological and radiological features and therapeutic responses. Between 2002 and 2012, four HIV1-infected patients with T1 stage of KS presented disseminated osseous lesions (Table 1). Mean age was 43 years (range 39 - 47 years), mean time of follow up until our analysis was 48.5 months (SD 53.8), and mean CD4 count at KS diagnosis was 190.5 c/mL (SD 202.8). All patients showed hypodense bone lesions predominating the axial skeleton (Figure 1), but no radiological imaging was performed to search for peripheral bone lesions.No patient reported pain or experienced pathological fractures. In one patient a dual-energy X-ray absorptiometry (DXA) showed a bone mineral density within normal range after 10 years of KS diagnosis with disseminated bone lesions. No radiological change was observed in that patient despite stable KS disease after 13 cycles of liposomal doxorubicin and ART (Figure 1).

We describe a well-documented long-term follow up of disseminated osseous AIDS-associated KS disease. In our four cases, lytic bone lesions were asymptomatic and were not associated with bone fragility. We even could confirm the KS nature of the lesions by bone biopsy in patient B (3 months after KS diagnosis), as the differential diagnosis is wide, and include bacillary angiomatosis, cancers or metastasis. Chemotherapy and antiretroviral treatment did not affect bone lesions using CT scan despite a good response on other KS-affected sites. Prognostic factors are well established in AIDS-associated KS [2]; however disseminated bone disease does not seem to have an impact on disease evolution. A larger sample size is needed to confirm this hypothesis.

CONCLUSIONS:Failure of CD4 reconstitution during months 1-3 on cART fully accounted for incident PJP. In contrast, there were 1.6 additional KS cases per 1000 person-years during months 1-3 on cART, suggesting that immune reconstitution may contribute to the risk for AIDS-defining KS.

Eosinophilic panniculitis presenting with Kaposi's sarcoma-like plaques in a patient who is human immunodeficiency virus positive: a case report.

Abstract

INTRODUCTION: Eosinophilic panniculitis is an unusual type of panniculitis characterized by a prominent infiltration of subcutaneous fat with eosinophils without an exact etiopathogenesis. To the best of our knowledge, up to now eosinophilic panniculitis has been described in only one previous case with human immunodeficiency virus disease in the literature.

CASE PRESENTATION:

Here we report the case of a 44-year-old Caucasian man, who is human immunodeficiency virus positive, diagnosed with eosinophilic panniculitis. A dermatological examination revealed multiple, confluent Kaposi's sarcoma-like purple colored, deep plaques and nodules on his right gluteal area and right thigh. The presence of the mixed inflammatory infiltrate of lymphocytes, macrophages, and numerous eosinophils involving both septa and lobules of the subcutis were noted on the histopathological examination. On the basis of all these clinical and histopathological findings the patient was diagnosed with eosinophilic panniculitis. He was given intravenous 60mg/day methylprednisolone for 3 consecutive days a week for 6 months. The lesions resolved almost completely after 6 months.

CONCLUSION:

The predominance of T helper-2 subset of T helper cells and the consequential increase in interleukin-5 cytokines accompanying peripheral eosinophilia and high serum immunoglobulin E levels may all be blamed for the development of eosinophilic panniculitis in our case study. As a result, we aim to emphasize that eosinophilic panniculitis should be kept in mind in the differential diagnosis of subcutaneous nodular lesions in patients who are human immunodeficiency virus positive. We also focus on the requirement of histopathological examination for the definitive diagnosis because the clinical features of eosinophilic panniculitis may easily be confused with Kaposi's sarcoma.

Source

Abstract

KSHV entry into human dermal microvascular endothelial cells (HMVEC-d), a natural in vivo target cell, via macropinocytosis is initiated through a multistep process involving binding of KSHV envelope glycoproteins with cell surface α3β1, αVβ3 and αVβ5 integrin molecules and tyrosine kinase EphrinA2 receptor followed by the activation of integrin-associated pre-existing signaling molecules such as FAK, Src, c-Cbl, PI3-K and Rho-GTPases. Many viruses, including KSHV, utilize cellular reactive oxygen species (ROS) for viral genomic replication and survival within host cells; however, the role of ROS on early events of viral entry and induction of signaling has not been elucidated. Here we show that KSHV induced ROS production very early during infection of HMVEC-d cells which was sustained over the observed 24 h post-infection. ROS induction was dependent on KSHV binding to the target cells since pretreatment of virus with heparin abolished ROS induction. Pretreatment of HMVEC-d cells with the antioxidant N-Acetyl-Cysteine (NAC) significantly inhibited KSHV entry and consequently gene expression without affecting virus binding. In contrast, H(2)O(2) treatment increased KSHV entry and infection. In addition, NAC inhibited KSHV infection induced translocation of αVβ3 integrin into lipid rafts, actin dependent membrane perturbations such as blebs observed during macropinocytosis and activation of EphrinA2 receptor, FAK, Src and Rac1 signal molecules. In contrast, H(2)O(2) treatment increased the activation of EphrinA2, FAK, Src and Rac1. These studies demonstrate that KSHV infection induces ROS very early during infection to amplify the signaling pathways necessary for its efficient entry via macropinocytosis in HMVEC-d cells.

Sirolimus for the treatment of kaposi sarcoma after renal transplantation: a series of 10 cases.

Source

Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia.

Abstract

The incidence of Kaposi sarcoma (KS) has substantially increased among immunocompromised patients, suggesting a role for immunosuppressive drugs. The aim of this study was to evaluate the incidence, features, and outcome of KS among 307 kidney transplantation patients at our center between January 1994 and June 2010. During the study period, the 10 patients who developed KS (3.25%) showed a mean age at transplantation of 35.8 ± 8.7 years (range, 22 to 49 years). The mean interval between transplantation and occurrence of KS was 24.7 ± 21.36 months (range, 6 to 64 months). The mean time of antithymocyte globulin induction was 9.5 days (range, 6 to 13 days). KS was restricted to the skin in 7 cases, among which, one presented with associated Hodgkin lymphoma. Visceral involvement (one lung and one colon) was observed in two cases. One patient presented with a gastric KS without skin lesions. Immunosuppressive treatment was reduced, then withdrawn in three cases, resulting in regression of KS a few weeks later, but with graft loss requiring hemodialysis at 1, 3 and 4 months. Among the remaining 7 cases, we stopped mycophenalate mofetil (MMF) and switched from calcineurin inhibitors to sirolimus. Allograft function remained stable after the switch. Only one patient who already had allograft dysfunction due to biopsy-proven chronic allograft nephropathy. Deteriorated progressively, undergoing hemodialysis at 2 years after KS diagnosis. In conclusion, we observed a relatively high incidence of KS among our cases. The introduction of sirolimus resulted in complete regression of KS lesions with preserved graft function.

Source

Abstract

Kaposi's sarcoma (KS) is the most common human immunodeficiency virus (HIV) infection disease-associated malignancy. It consists of an angiosarcomatous change of the epithelial and mucous membrane-associated connective tissue not only in various sites, for example, skin, gastrointestinal system, lungs, and so on, but may also involve nonepithelial organs, such as lymph nodes. An unusual localization of KS to an intramammary lymphnode is reported here. The patient, an HIV-negative 69-year-old woman with a clinical history of rheumatoid arthritis treated with hydrocortisone, had an 8-month pathological history of biopsy-proven Kaposi sarcoma of the skin with visceral extension (stomach and duodenum). The appearance of a well-defined 23 × 20 mm(2) breast nodule during chemotherapy elicited fine-needle cytology to exclude breast carcinoma. Surgical excision confirmed the cytopathological diagnosis of Kaposis'ssarcoma.

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About Me

Am old enough to understand the difference between the Bay of Pigs - and roasting a pig at a epicurian feast. Been thru the hippy, yippie and yuppie years - always remaining who I am.
Very much believe in "Sing your own song - weave your own tapestry"
Am young enough to still know the thrill of new discoveries, the beauty of the evening, to celebrate the joy of another tommorow.
Survived these many decades with a severe medical problems. Sorting out the maze of now having two lymphomas and all their nasty little companions, but I continue.
Besides, being a simple iconoclastic eclectic, have been called many things. An incurable romanticist - with a strong touch of reality. Thinker, intellectual (God, how I hate that term) - been told I am a lion with the heart of the poet.
Know how to wage war and conquer my foes - but would rather be known as one who brings hope and life. To bring hope into anothers life is the ultimate of joys.
Life should be about bringing hope, peace, vision... a sense of purpose beyond yourself.